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STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor.

Perry ST, Buck MD, Lada SM, Schindler C, Shresta S - PLoS Pathog. (2011)

Bottom Line: High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication.Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression.Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1.

View Article: PubMed Central - PubMed

Affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

ABSTRACT
Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.

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Survival of mice following infection with DENV.Survival was monitored for at least 30 days in mice infected i.v. with DENV2 strain S221. (A) Mice were infected with 1010 GE (WT n = 8; STAT1−/− n = 12; STAT2−/− n = 17; STAT1−/−/2−/− n = 14; AG129 n = 13). Differences in survival were statistically different (**, p<0.005) between STAT1−/−/2−/− and AG129 mice. (B) Mice were infected with 1011 GE (n = 9) or 1012 GE of DENV (n = 5). (C) Mice were infected with 1010 GE (STAT1−/−/AR−/− n = 12; STAT1−/−/GR−/− n = 8).
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ppat-1001297-g001: Survival of mice following infection with DENV.Survival was monitored for at least 30 days in mice infected i.v. with DENV2 strain S221. (A) Mice were infected with 1010 GE (WT n = 8; STAT1−/− n = 12; STAT2−/− n = 17; STAT1−/−/2−/− n = 14; AG129 n = 13). Differences in survival were statistically different (**, p<0.005) between STAT1−/−/2−/− and AG129 mice. (B) Mice were infected with 1011 GE (n = 9) or 1012 GE of DENV (n = 5). (C) Mice were infected with 1010 GE (STAT1−/−/AR−/− n = 12; STAT1−/−/GR−/− n = 8).

Mentions: Mice lacking type I and type II IFN receptors (AG129), but not their wild type or single-deficient counterparts, are highly susceptible to DENV infection and display an early death phenotype when infected with the DENV serotype 2 (DENV2) strain S221 [25]–[27]. In agreement with published studies showing that type I and type II IFNs restrict DENV infection in mice [24], [26], 12 of 13 AG129 mice died by day 8 following infection with 1010 genomic equivalents (GE) (≈2×105 PFU) of the DENV2 strain S221 [28], [29] (Figure 1A). Although the STAT1 protein is a critical component of both type I and II IFN receptor pathways, mice lacking STAT1 are able to clear DENV infection [24]. Because STAT2-dependent activity has been previously demonstrated downstream of both type I and type II IFN receptors in the absence of STAT1 [30], [31], we hypothesized STAT2 was involved in an IFN-dependent STAT1-independent mechanism of protection against DENV. To assess the contribution of STAT2 to the STAT1-independent control of DENV infection in vivo, STAT1−/−/2−/− double knockout mice were generated by intercrossing single-deficient animals, and also infected with 1010 GE S221. At this dose of virus, 90–100% of wild type and congenic single-deficient mice lacking either STAT1 or STAT2 survived DENV infection. However, all mice with a combined deficiency of STAT1 and STAT2 displayed the early death phenotype observed in AG129 mice and succumbed to DENV infection within 4–6 days, demonstrating the importance of STAT2 to the STAT1-independent mechanism of protection against DENV infection in vivo (Figure 1A). The median survival of STAT1−/−/2−/− mice was significantly lower than AG129 at this virus dose (p = 0.0013; **), indicating the absence of both STAT1 and STAT2 renders these mice more susceptible to DENV-mediated disease than the combined loss of type I and II IFN receptors.


STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor.

Perry ST, Buck MD, Lada SM, Schindler C, Shresta S - PLoS Pathog. (2011)

Survival of mice following infection with DENV.Survival was monitored for at least 30 days in mice infected i.v. with DENV2 strain S221. (A) Mice were infected with 1010 GE (WT n = 8; STAT1−/− n = 12; STAT2−/− n = 17; STAT1−/−/2−/− n = 14; AG129 n = 13). Differences in survival were statistically different (**, p<0.005) between STAT1−/−/2−/− and AG129 mice. (B) Mice were infected with 1011 GE (n = 9) or 1012 GE of DENV (n = 5). (C) Mice were infected with 1010 GE (STAT1−/−/AR−/− n = 12; STAT1−/−/GR−/− n = 8).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040673&req=5

ppat-1001297-g001: Survival of mice following infection with DENV.Survival was monitored for at least 30 days in mice infected i.v. with DENV2 strain S221. (A) Mice were infected with 1010 GE (WT n = 8; STAT1−/− n = 12; STAT2−/− n = 17; STAT1−/−/2−/− n = 14; AG129 n = 13). Differences in survival were statistically different (**, p<0.005) between STAT1−/−/2−/− and AG129 mice. (B) Mice were infected with 1011 GE (n = 9) or 1012 GE of DENV (n = 5). (C) Mice were infected with 1010 GE (STAT1−/−/AR−/− n = 12; STAT1−/−/GR−/− n = 8).
Mentions: Mice lacking type I and type II IFN receptors (AG129), but not their wild type or single-deficient counterparts, are highly susceptible to DENV infection and display an early death phenotype when infected with the DENV serotype 2 (DENV2) strain S221 [25]–[27]. In agreement with published studies showing that type I and type II IFNs restrict DENV infection in mice [24], [26], 12 of 13 AG129 mice died by day 8 following infection with 1010 genomic equivalents (GE) (≈2×105 PFU) of the DENV2 strain S221 [28], [29] (Figure 1A). Although the STAT1 protein is a critical component of both type I and II IFN receptor pathways, mice lacking STAT1 are able to clear DENV infection [24]. Because STAT2-dependent activity has been previously demonstrated downstream of both type I and type II IFN receptors in the absence of STAT1 [30], [31], we hypothesized STAT2 was involved in an IFN-dependent STAT1-independent mechanism of protection against DENV. To assess the contribution of STAT2 to the STAT1-independent control of DENV infection in vivo, STAT1−/−/2−/− double knockout mice were generated by intercrossing single-deficient animals, and also infected with 1010 GE S221. At this dose of virus, 90–100% of wild type and congenic single-deficient mice lacking either STAT1 or STAT2 survived DENV infection. However, all mice with a combined deficiency of STAT1 and STAT2 displayed the early death phenotype observed in AG129 mice and succumbed to DENV infection within 4–6 days, demonstrating the importance of STAT2 to the STAT1-independent mechanism of protection against DENV infection in vivo (Figure 1A). The median survival of STAT1−/−/2−/− mice was significantly lower than AG129 at this virus dose (p = 0.0013; **), indicating the absence of both STAT1 and STAT2 renders these mice more susceptible to DENV-mediated disease than the combined loss of type I and II IFN receptors.

Bottom Line: High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication.Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression.Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1.

View Article: PubMed Central - PubMed

Affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

ABSTRACT
Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.

Show MeSH
Related in: MedlinePlus